The primary objective of this proposal is to investigate the mechanisms by which the Wnt-Axin signaling network regulates mammary gland development and breast cancer. Wnt signals control key developmental processes and several Wnt signaling molecules have been implicated in the development of different forms of cancer. Wnt signaling has been well established to play an important role in normal development as well as neoplastic transformation of the mammary gland. We have demonstrated previously that Axin negatively modulates a Wnt signal that is required for lobulo-alveolar development in late pregnancy. High levels of Axin induce mammary epithelia to undergo apoptosis. In addition, mutations of Axin that lead to constitutive activation of the Wnt signaling pathway have been linked to many different forms of human cancers, including breast cancer. Therefore, the Wnt-Axin signaling network is critical for mammary gland development in health and disease. Breast cancers remain the major leading cause of cancer mortality in women. Numerous studies have repeatedly confirmed that reproductive history represents the strongest risk/protective factor for breast cancer. Pregnancy at an early age confers a 50% reduction in lifetime risk of breast cancer as compared with nulliparous women. The protective effect of early pregnancy provides an operative model to achieve breast cancer prevention and therapy in humans. However, very little is known about fundamental changes of the mammary gland during pregnancy and lactation. A recent study showed that the parity-induced mammary epithelial progenitors contribute to differences in cellular composition between the nulliparous and parous glands. This newly identified progenitor population, displaying stem cell characteristics, may provide insight toward the protective factor(s) associated with pregnancy and lactation. To investigate the involvement of the Wnt-Axin signaling network in mammary gland development and tumorigenesis, we will elucidate the mechanisms by which the Axin mutant induces breast cancer. The inhibitory effect of Axin on mammary gland development suggests that it might interfere with malignant transformation induced by oncogenic signaling pathways. We will explore the role of the Axin tumor suppressor in mammary tumorigenesis. We have recently developed a mouse transgenic system, which is ideal to manipulate gene activity specifically in the adult mammary stem cell. Using this novel approach, we will determine the role of the Wnt-Axin signaling network in the parity-induced mammary epithelial progenitors, reflecting their refractoriness to breast cancer.